Assessment of malaria whole organism vaccines

National Institute Of Allergy And Infectious Diseases

Investigators

Linked publications, trials & patents

Abstract

From our publications, we report the following FY2023 advances: Chavtur C, Staubus WJ, Ho M, Hergott DEB, Seilie AM, Healy SA, Duffy PE, Jackson L, Talley A, Kappe SHI, Hoffman SL, Richie TL, Kublin JG, Chang M, Murphy SC. Plasmodium 18S Ribosomal RNA Biomarker Clearance After Food and Drug Administration-Approved Antimalarial Treatment in Controlled Human Malaria Infection Trials. 2023. Open Forum Infect Dis. Apr 13;10(5):ofad202. doi: 10.1093/ofid/ofad202. Sensitive molecular assays, such as quantitative reverse-transcription polymerase chain reaction (qRT-PCR) of Plasmodium 18S ribosomal RNA (rRNA), are increasingly the primary method of detecting infections in controlled human malaria infection (CHMI) trials. However, thick blood smears (TBSs) remain the main method for confirming clearance of parasites after curative treatment, in part owing to uncertainty regarding biomarker clearance rates. This collaborative project led by University of Washington compiled 18S rRNA qRT-PCR data from 127 Plasmodium falciparuminfected participants treated with chloroquine or atovaquone-proguanil in 6 CHMI studies conducted in Seattle, Washington, over the past decade. We used a survival analysis approach to compare biomarker and TBS clearance times among studies. The effect of the parasite density at which treatment was initiated on clearance time was estimated using linear regression. The median time to biomarker clearance was 3 days (interquartile range, 35 days), while the median time to TBS clearance was 1 day (12 days). Time to biomarker clearance increased with the parasite density at which treatment was initiated. Parasite density did not have a significant effect on TBS clearance. We concluded the Plasmodium 18S rRNA biomarker clears quickly and can be relied on to confirm the adequacy of Food and Drug Administrationapproved treatments in CHMI studies at nonendemic sites. Richie TL, Church LWP, Murshedkar T, Billingsley PF, James ER, Healy SA, Diawara H, Sissoko MS, Sagara I, Cook DM, Mordmller B, Chakravarty S, Kapulu M, Kreidenweiss A, Vaughan A, Kublin J, Murphy S, Jongo S, Tanner M, Sirima S, Laurens M, Daubenberger C, Silva J, Lyke KE, Abdulla S, Dicko A, Kappe S, Sim BKL, Kremsner PG, Duffy PE, Hoffman SL. Sporozoite Immunization: Innovative Translational Science to Support the Fight Against Malaria. 2023. Expert Review of Vaccines. In press. doi:10.1080/14760584.2023.2245890 A highly effective malaria vaccine is urgently needed, especially for Plasmodium falciparum (Pf), the deadliest human malaria parasite. Sporozoites (SPZ), the parasite stage transmitted by Anopheles mosquitoes to humans, are the only vaccine immunogen achieving > 90% efficacy against Pf infection. We and our partners in the PfSPZ Consortium reviewed > 30 clinical trials of PfSPZ vaccines in the U.S.A., Europe, Africa, and Asia, based on first-hand knowledge of the trials and PubMed searches of 'sporozoites,' 'malaria,' and 'vaccines.' First generation (radiation-attenuated) PfSPZ vaccines are safe, well tolerated, 80-100% efficacious against homologous controlled human malaria infection (CHMI) and provide 18-19 months protection without boosting in Africa. Second generation chemo-attenuated PfSPZ are more potent, 100% efficacious against stringent heterologous (variant strain) CHMI, but require a co-administered drug, raising safety concerns. Third generation, late liver stage-arresting, replication competent (LARC), genetically-attenuated PfSPZ are expected to be both safe and highly efficacious. Overall, PfSPZ vaccines meet safety, tolerability, and efficacy requirements for protecting pregnant women and travelers, with licensure for these populations possible within five years. Protecting children and mass vaccination programs to block transmission and eliminate malaria are long-term objectives. In unpublished work, we continued progress on our IND clinical trials registered at clinicaltrials.gov: WOCBP PfSPZ Vaccine in Mali, Africa #19-I-N113 This was a randomized, double blind, placebo-controlled study to assess the safety, tolerability, immunogenicity, and protective efficacy of PfSPZ Vaccine in healthy women of child bearing potential (WOCBP). Enrolled women receive pregnancy prevention during vaccination, but report plans to become pregnant in the near future. The study assessed safety, tolerability and efficacy of PfSPZ Vaccine primary series in healthy Malian WOCBP when administered at 1, 8, 29 days at two different doses (9 x105and 1.8 x106) after receiving antimalarials to clear parasitemia. This study enrolled in FY19, and showed that a 1-month PfSPZ Vaccine regimen could induce durable protection for 2 years, and also that pre-conception PfSPZ Vaccine can confer protection against pregnancy malaria to women who conceived during the 2 years after primary vaccine series. This findings have been submitted to a journal for review. PfSPZ CVac-Mali #19-I-0099 We previously reported the CVac-PYR2 #17-I-0067 study of Chemoprophylaxis Vaccination (CVac) at NIH: high dose PfSPZ-CVac PfSPZ Challenge NF54 with either pyrimethamine (PYR) or chloroquine (CQ) were safe and well-tolerated. In both PfSPZ-CVac-PYR and PfSPZ-CVac-CQ groups, high levels of sterile immunity against homologous (NF54) and heterologous (7G8) CHMI were observed 3 months after last dose. The unprecedented results from #17-I-0067 justified a Phase 2 efficacy PfSPZ Cvac trial that began in Bancoumana, Mali (PfSPZ CVac-Mali #19-I-0099) in FY2019. The study has completed clinical activities and is undergoing analyses.